Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging

John C. Means, Bryan C. Gerdes, Simon Kaja, Nathalie Sumien, Andrew J. Payne, Danny A. Stark, Priscilla K. Borden, Jeffrey L. Price, Peter Koulen

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Mouse models of neurodegenerative diseases such as Alzheimer’s disease (AD) are important for understanding how pathological signaling cascades change neural circuitry and with time interrupt cognitive function. Here, we introduce a non-genetic preclinical model for aging and show that it exhibits cleaved tau protein, active caspases and neurofibrillary tangles, hallmarks of AD, causing behavioral deficits measuring cognitive impairment. To our knowledge this is the first report of a non-transgenic, non-interventional mouse model displaying structural, functional and molecular aging deficits associated with AD and other tauopathies in humans with potentially high impact on both new basic research into pathogenic mechanisms and new translational research efforts. Tau aggregation is a hallmark of tauopathies, including AD. Recent studies have indicated that cleavage of tau plays an important role in both tau aggregation and disease. In this study we use wild type mice as a model for normal aging and resulting age-related cognitive impairment. We provide evidence that aged mice have increased levels of activated caspases, which significantly correlates with increased levels of truncated tau and formation of neurofibrillary tangles. In addition, cognitive decline was significantly correlated with increased levels of caspase activity and tau truncated by caspase-3. Experimentally induced inhibition of caspases prevented this proteolytic cleavage of tau and the associated formation of neurofibrillary tangles. Our study shows the strength of using a non-transgenic model to study structure, function and molecular mechanisms in aging and age related diseases of the brain.

Original languageEnglish
Pages (from-to)2278-2288
Number of pages11
JournalNeurochemical Research
Volume41
Issue number9
DOIs
StatePublished - 1 Sep 2016

Keywords

  • Age-related cognitive decline
  • Molecular mechanisms in brain aging
  • Neurofibrillary tangles
  • Preclinical
  • Tauopathy

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